As atomics moves ahead, such radiotherapy as Cobalt-60, linear accelerators and electron beams has been one of major means to cancer therapy. However, conventional photon or electron therapy has been undergone physical restrictions of radioactive rays; for Embodiment, many normal tissues on a beam path will be damaged as tumor cells are destroyed. On the other hand, sensitivity of tumor cells to the radioactive rays differs greatly, so in most cases, conventional radiotherapy falls short of treatment effectiveness on radioresistant malignant tumors (such as glioblastoma multiforme and melanoma).
For the purpose of reducing radiation damage to the normal tissue surrounding a tumor site, target therapy in chemotherapy has been employed in the radiotherapy. While for high-radioresistant tumor cells, radiation sources with high RBE (relative biological effectiveness) including such as proton, heavy particle and neutron capture therapy have also developed. Among them, the neutron capture therapy combines the target therapy with the RBE, such as the boron neutron capture therapy (BNCT). By virtue of specific grouping of boronated pharmaceuticals in the tumor cells and precise neutron beam regulation, BNCT is provided as a better cancer therapy choice than conventional radiotherapy.
BNCT takes advantage that the boron (10B)-containing pharmaceuticals have high neutron capture cross section and produces 4He and 7Li heavy charged particles through 10B(n,α)7Li neutron capture and nuclear fission reaction. The two charged particles, with average energy at about 2.33 MeV, are of linear energy transfer (LET) and short-range characteristics. LET and range of the alpha particle are 150 keV/micrometer and 8 micrometers respectively while those of the heavy charged particle 7Li are 175 keV/micrometer and 5 micrometers respectively, and the total range of the two particles approximately amounts to a cell size. Therefore, radiation damage to living organisms may be restricted at the cells' level. When the boronated pharmaceuticals are gathered in the tumor cells selectively, only the tumor cells will be destroyed locally with a proper neutron source on the premise of having no major normal tissue damage.
BNCT is also well known for binary cancer therapy, for its effectiveness depending on the concentration of the boronated pharmaceuticals and the number of the thermal neutrons at the tumor site. Thus, besides improvement of flux and quality of the neutron source, the development of the boronated pharmaceuticals plays a significant role in BNCT researches.
It is known at present that, 4-(10B)borono-L-phenylalanine (L-10BPA) is an important boron containing drug for BNCT.
Therefore, various methods for the synthesis of L-BPA have been developed now. As shown in the following Formula (A), two synthesis approaches of L-BPA including formation (a) and formation (b) have been developed.

The approach demonstrated as formation (a) is by introduction of boronic acid group into phenylalanine, which is based on forming the C—B bond directly by the introduction of the dihydroxylboryl substituent to the phenylalanine fragment.
J. Org. Chem. 1998, 63, 8019 discloses a method undergoing palladium-catalyzed cross-coupling between an amine-protected L-4-iodophenylalanine, such as (S)—N-Boc-4-iodophenylalanine, and a diboron compound, such as bis-(pinacolato)diboron. L-BPA is then obtained after removal of the protecting group of amine and boronic acid of the phenylalanine.
However, an additional pre-method is further required for preparing the boronating agent, resulting in more time consumption and complicacy of the method, and thereby failing to prepare L-BPA in high yield. The prior art discloses that the carboxylic acid of (S)—N-Boc-4-iodophenylalanine reactant is protected into benzyl ester to improve the yield of the obtained protected L-BPA up to 88%. However, an additional step of removing the benzyl ester protecting group of the carboxylic acid of the protected L-BPA is further needed, which complicates the synthetic method.
Accordingly, the drawbacks of this method also include the additional pre-method for preparing the boronating agent as mentioned above, and further include the time-consuming and multi-step synthesis involving the protection step of the carboxylic acid and the deprotection step of the carboxylic acid afterwards.
Another approach demonstrated as formation (b) involving coupling reaction between an amino acid and a boron-containing benzyl or benzaldehyde fragment is also developed.
Biosci. Biotech. Biochem. 1996, 60, 683 discloses an enantioselective synthesis of L-BPA by coupling cyclic ethers of boronic acid and a chiral derivative from L-valine, wherein the cyclic ethers of boronic acid are prepared from 4-boronobenzylbromide in advance. However, the last synthetic step of the method readily results in undesired racemization of the amino acid. Thus, an enzymatic resolution step, which typically reduces the production yield, is required to obtain optically-pure L-BPA.
Accordingly, the drawbacks of this method still include the additional pre-method for preparing the boronating agent, resulting in more time consumption and complicacy of the method, and thereby failing to prepare L-BPA in high yield.
Besides, 10B contained in L-BPA is known as the critical factor accumulated in tumor cells and subsequently irradiated with thermal neutron. Thus 10B renders L-BPA a treatment of cancer through boron neutron capture therapy (BNCT).
However, natural boron exists as 19.9% of 10B isotope and 80.1% of 11B isotope. Therefore, many researchers have been developing synthetic methods suitable for producing L-BPA, and preferably suitable for producing 10B-enriched L-BPA.
As disclosed in J. Org. Chem. 1998, 63, 8019 mentioned above, the conventional methods comprise multi-step syntheses of the boronating agents, which reduce a large amount of 10B-enriched materials during the method. As a result, the methods are not suitable for producing 10B-enriched L-BPA.
As disclosed in Biosci. Biotech. Biochem. 1996, 60, 683 mentioned above, an optically pure L-BPA is not obtained until the enzymatic resolution step, and also the multi-step syntheses of the boronating agent render the transformations of the 10B-enriched materials during the method. Hence, the conventional method is not suitable for producing 10B-enriched L-BPA as well.
Furthermore, Bull. Chem. Soc. Jpn. 2000, 73, 231 discloses a method based on coupling 4-iodo-L-phenylalanine and pinacolborane in the presence of palladium catalyst. However, since the prior art is silent on how to produce 10B-enriched L-BPA and also 10B-enriched pinacolborane is not commercially available, the method is not suitable for producing 10B-enriched L-BPA, either.
In addition, Synlett. 1996, 167 discloses a method by coupling iodophenylborate and L-serine zinc derivatives. The method involves indispensable pre-preparation of the L-serine zinc derivatives and the pre-preparation of the iodophenylborate, thereby giving a low yield of L-BPA. Besides, the method is still not suitable for producing 10B-enriched L-BPA, for both 10B-enriched BI3 and 1,3-diphenylpropane-1,3-diol adopted in the method are not commercially available.
The statements in this section merely provide background information related to the present disclosure and may not constitute prior art.